Differences in Lung Cancer Risk Between
Men and Women: Examination of the Evidence
Edith A. Zang, Ernst L. Wynder*
It is a well-established fact that cigarette smoking is the principal cause of lung cancer in both men and women. The continued higher incidence rates in men reflect their longer and
greater exposure to cigarette tar (/).
A pattern has evolved during the past decade in the United
States showing that, while lung cancer incidence is leveling off
among men, it is continuing to rise at a steady rate among
women (2). In fact, there has been a 500% increase in female
lung cancer mortality since 1950 (3), surpassing breast cancer as
the leading cause of cancer deaths among U.S. women since
1987 (4). At the same time, because of the slower decline in
smoking prevalence among women than among men (/), the exposure of women to tobacco carcinogens has gradually approached and, in fact, may soon surpass that of men (2).
Consequently, if current trends continue, the lung cancer rates
among women are expected to surpass those among men within
the next two to three decades.
In light of these trends, recent epidemiologic findings (5-13),
which suggest that, dose for dose, women may be more susceptible to tobacco carcinogens than men, are of concern. In fact,
the rate of decrease in the gap between male-female lung cancer
rates observed during the past three decades is more pronounced
than would be expected on the basis of the changing trends in
male and female smoking rates alone. Although the issue of a
higher susceptibility to tobacco carcinogens by female smokers
is still inconclusive, the potential public health consequences of
such a phenomenon would be substantial.
Our previous work (8), suggesting that women may be more
susceptible to tobacco carcinogens than men, was limited to a
broad histologic classification of lung cancer, i.e., Kreyberg I
and Kreyberg II types. It is important to further evaluate this
finding by using more precise histologic subtypes. In 1985, we
started collecting more detailed smoking histories from the
study participants. As a result, we now have more precise quantitation of lifelong smoking exposure for each participant based
on as many as seven different brands of cigarettes smoked.
Spurred by our initial findings (8) and by the availability of
additional data on more case subjects as well as control subjects
(with more detailed and precisely quantitated smoking exposures and more defined lung cancer histologies), we conducted an in-depth evaluation of the differences in lung cancer
risk between men and women. By reviewing the results of
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Background: Lung cancer incidence is gradually leveling off
in U.S. men but is continuing to rise in U.S. women. This increase in U.S. women exceeds that expected from a slower
decline of smoking among women. Recent epidemiologic and
biochemical studies suggest gender differences in susceptibility to tobacco carcinogens. Purpose: We conducted an
up-to-date, more in-depth evaluation of our earlier observation of a potential gender difference in relative risk (RR) of
lung cancer due to smoking. We added information from
several additional case and control subjects and included
more precise histologic classification of the cancer type, accurate quantitation of smoke exposure, and adjustments for
body size. Methods: The present investigation was a part of
an ongoing hospital-based, case-control study by the
American Health Foundation. It included data from 1889
case subjects (1108 males and 781 females) with lung cancer
of squamous/epidermoid, small-cell/oat cell, large-cell, and
adenocarcinoma types and 2070 control subjects (1122 males
and 948 females) with diseases unrelated to smoking. The
case and control subjects were admitted to participating
hospitals from 1981 to 1994 and were pair-matched by age,
sex, hospital, and the time of hospital admission. Ex-smokers
and non-Caucasians were excluded from analyses to avoid
confounding. The RRs and 95% confidence intervals were
estimated from adjusted odds ratios (ORs) by use of unconditional multiple logistic regression analysis, and statistical
significance was determined by two-sided tests. The ORs for
major histologic types were estimated at increasing levels of
exposure to cigarette smoke. Results: Our results indicated
that women were more likely to be never-smokers than men,
particularly those with the squamous/epidermoid-type cancer (8.3% for women versus 2.9% for men 55 years old or
older). Men started smoking earlier, reported inhaling more
deeply, and smoked more cigarettes per day than women. In
contrast, dose-response ORs over cumulative exposure to
cigarette smoking were 1.2-fold to 1.7-fold higher in women
than in men for the three major histologic types; these differences were more pronounced for small-cell/oat cell carcinomas and adenocarcinomas than for squamous/
epidermoid carcinomas. Adjustments for weight, height, or
body mass index did not alter the ORs. Conclusions: These
results confirm our earlier finding that the ORs for major
lung cancer types are consistently higher for women than for
men at every level of exposure to cigarette smoke. Furthermore, this gender difference cannot be explained by differences in base-line exposure, smoking history, or body size,
but it is likely due to the higher susceptibility to tobacco carcinogens in women. [J Natl Cancer Inst 1996;88:183-92]
*'Affiliation of authors: American Health Foundation, New York, NY.
Correspondence to: Edith A. Zang, Ph.D., American Health Foundation, 320
East 43rd St., New York. NY 10017.
See "'Notes" section following '"References."
Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996
ARTICLES
183
relevant laboratory studies and other epidemiologic investigations conducted during the past two decades, we also attempted
to evaluate the biological plausibility of our hypothesis of differential gender-related susceptibility to tobacco carcinogens.
Subjects and Methods
The data were derived from a large, ongoing, hospital-based, case-control
study by the American Health Foundation of tobacco-related cancers: this study
was described elsewhere (14). The study sample included lung cancer case subjects and control subjects, admitted to 26 participating hospitals in six cities
during the period 1981 to 1994. Since ex-smokers represent a heterogeneous
group with regard to prior exposure that is difficult to adjust for, we excluded
them from the analyses to avoid distorting the exposure measures. We also excluded non-Caucasians, constituting only about 10% of case and control subjects
in our data, since their smoking and quitting patterns (15) and their susceptibility
to tobacco carcinogens (16) are believed to differ from those of whites and
could, therefore, bias the male-female comparisons.
All data were collected using a standardized questionnaire completed by
trained interviewers. The questionnaire included detailed questions on demographics, smoking history, medical history, occupational history, and diet.
Case Subjects
Control Subjects
The control subjects (1122 males and 948 females) were patients who had
been diagnosed with non-tobacco-related diseases (i.e.. cancers of the reproductive system (prostate, cervix, or ovaries] and digestive system, leukemia and
lymphoma. and non-neoplastic diseases such as injuries [fractures or disc
problems], kidney or urinary bladder infections, arthritis, hernia, and eye diseases). All disease categories among the control subjects had similar malefemale distributions, except in the category of cancers of reproductive organs
(30% in females and 8% in males). In addition, more males than females had
cancers of the digestive organs (23% of the males versus 13% of the females)
and kidney or urinary bladder infections (5% versus 1%). as well as hernia (4%
versus 1%). Each control subject was individually matched to a case subject according to age (±5 years), sex. hospital, and time of hospital admission.
The smoking histories included the following information for each brand of
cigarettes smoked: number of cigarettes smoked per day, duration of smoking,
and cigarette brand, starting with the most recent brand. From 1981 to 1984, the
questionnaire provided space to list up to only four different brands of cigarettes;
in subsequent years, however, information on up to seven brands of cigarettes
could be listed. Whenever in an individual's lifetime the number of different
brands smoked exceeded these limits, the earlier brands that could not be listed
individually were combined into a single item by averaging their tar yield and
cigarettes smoked per day and summing their duration of smoking.
Ever-smokers were defined as those who had ever smoked at least one
cigarette per day for 1 year. Current smokers were those who had smoked within
the past year. Never-smokers were those who had never smoked cigarettes
regularly. Ex-smokers were quitters who had not smoked within the past year.
Data on tar yield for various cigarette brands were obtained from the 1977
and 1988 Federal Trade Register (18) for patients admitted to the hospital from
1981 to 1984 and from 1985 to 1994, respectively. This information was entered
into the computer and subsequently linked by a computer program with the appropriate brands of cigarettes smoked in each participant's smoking history.
Statistical Methods
The cumulative index that measures lifetime exposure to tar through cigarette
smoking (71 is computed by summing over the different brands smoked (B): the
products of tar content in milligrams ((), the duration (in days) of smoking (D),
and the number of cigarettes consumed per day (C) for that brand (/'). The result
is converted into kilograms:
The relative risks (RRs) for squamous/epidermoid carcinoma and adenocarcinoma, at various levels of exposure, measured in number of cigarettes smoked
per day, pack-years, and cumulative tar, were estimated through adjusted odds
ratios (ORs) with 95% confidence intervals (CIs), using unconditional multiple
logistic regression analysis (19). The unconditional model was chosen because
case and control subjects were no longer pair-matched because of the exclusion
from our data of quitters, smokers of pipes and cigars, and those with incomplete
smoking histories. Adjustment of the ORs was accomplished by including one or
more continuously measured covariates, such as age, weight, height, or body
mass index (BMI), grouped into quintiles and coded as 0-4, in the logistic
regression model. BMI was calculated from body weight and height by use of
the following formula: BMI = kg/cm2. ORs were calculated separately for each
level of exposure (coded as 1): never-smokers were the referent category (coded
as 0). Alternatively, dose-response ORs were calculated by use of five levels of
exposure to cigarette smoke as continuous factors; these levels were coded as 04, and 0 represented the referent category. Since the logistic model implies that
the logit of risk is a linear function of exposure (.v), the relative odds for individuals with exposure level .v, compared with individuals with exposure level
-*o is
OR, = exp[p(.v,-.v0)].
Thus, if P>0. the OR for dose-response estimates the increase in relative odds of
disease with each increasing level of exposure.
ORs were considered to be statistically significant if their 95% CIs did not
enclose 1.0. The statistical significance of the difference between pairs of ORs
was evaluated using the heterogeneity chi-squared test applied to the logarithm
of the ORs. as described by Gart (20) and Sheehe (21).
Table 1. Distribution of lung cancer by histologic type and gender
Results
No. (%)
184
Histologic type
Males
(n= 1156)
Females
(n = 831)
Characteristics of Study Population
Squamous/epidermoid carcinoma
Small-cell/oat cell carcinoma
Large-cell carcinoma
Adenocarcinoma
Bronchiolar and alveolar cell carcinomas
Mixed/other cancers
397 (34.3)
182(15.7)
111 (9.6)
418(36.2)
17(1.5)
31(2.7)
165(19.9)
142(17.1)
90(10.8)
384 (46.2)
30(3.6)
20 (2.4)
The distribution of lung cancer histologic types, by gender, is
presented in Table 1. The relative frequency of the squamous/
epidermoid-type carcinoma was substantially higher in males
than in females (34.3% in males versus 19.1% in females),
while adenocarcinoma and bronchiolar and alveolar cell carcinomas had higher relative frequencies among females (46.2%
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Lung cancer cases are broken down by histologic type as shown in Table I.
In the analyses, we first categorized lung cancer cases into squamous/epidermoid
carcinoma (397 male and 165 female case subjects), small-cell/oat cell carcinoma (182 male and 142 female case subjects), and adenocarcinoma (418 male
and 384 female case subjects). Alternatively, we also used the broader classification of Kreyberg I (including squamous/epidermoid, small-cell/oat cell, and
large-cell carcinomas) (690 male and 397 female case subjects) and Kreyberg II
(including adenocarcinoma and bronchiolar and alveolar cell carcinomas) (435
male and 414 female case subjects) (17). The numbers of small-cell/oat cell cancer case subjects were not adequate to be included for the more detailed
analyses. Lung cancer case subjects with histologies classified as mixed or
other, representing less than 3% of all case subjects, were excluded from the
analysis.
Smoking History
among females versus 36.2% among males and 3.6% among
females versus 1.5% among males, respectively). The distributions of small-cell/oat cell, large-cell, and mixed/other cancers,
on the other hand, were similar in the two sexes.
As a result of age matching, approximately 90% of both case
and control subjects were 45 years old or older (Table 2). Control subjects tended to be more highly educated than case subjects among both sexes, and males were more likely to be
professionals than females. Among both the case and control
subjects, more men than women were married, and more women
than men were widowed. Further analysis showed the highest
proportions of case subjects to be found among divorced/
separated men (22.9% for never-smokers and 72.4% for current
smokers) and widowed women (16.8% for never-smokers and
77.0% for current smokers).
Smoking Habits of Study Population
Lung Cancer Risk by Exposure to Cigarette Smoke in
Current Smokers
Age-adjusted ORs for squamous/epidermoid carcinoma and
adenocarcinoma were calculated at increasing levels of exposure to cigarette smoke. Exposure was expressed as cumulative tar, pack-years, and current number of cigarettes smoked
per day. The number of small-cell/oat cell carcinomas (182
males and 142 females) was too low to compute separate RR estimates at individual levels of exposure; therefore, only doseresponse ORs were calculated for this third histologic type.
Table 4 lists the ORs for developing squamous/epidermoid
carcinoma of the lung in current smokers versus never-smokers.
The ORs at each exposure level were consistently higher for
women than for men, except at the lowest level of cumulative
exposure to tar, although the 95% CIs for individual ORs overlapped between the sexes. The three dose-response ORs were
1.2-fold to 1.5-fold higher for women, and the gender differences were significant over both cumulative exposure to tar (3.2
for women versus 2.1 for men) and number of cigarettes smoked
per day (2.9 versus 2.1), but not significant over pack-years of
exposure (3.0 versus 2.6).
Because of a higher proportion of never-smokers with
adenocarcinoma, the estimated RR for this cancer was consistently lower in both sexes compared with the squamous/epider-
Table 2. Characteristics of study population
Males
Squamous/
epidermoid
carcinoma
(n = 397), %
Age,y
<45
45-54
55-64
>65
Females
Adenocarcinoma
(n = 418), c,h
Small-cell/
oat cell
carcinoma
(n=l82), %
6.6
22.2
40.3
31.0
14.1
24.6
38.0
23.2
Marital status
Single
Married
Separated/divorced
Widowed
7.8
74.8
9.8
7.6
Education, y
<12
12
13-16
>16
Occupation
Professional
Skilled
Unskilled
Housewife
Characteristic
Controls
(n= 1122),%
Squamous/
epidermoid
carcinoma
(n= 165),%
5.5
22.0
47.8
24.7
10.6
18.5
39.0
31.8
8.6
79.0
8.6
3.8
6.6
73.1
14.3
6.0
34.3
28.8
25.5
11.4
25.7
25.5
34.1
14.7
27.0
44.8
28.2
—
36.1
43.5
20.3
—
Adenocarcinoma
(n = 384), %
Small-cell/
oat cell
carcinoma
(n= 142),%
Controls
(n = 948), %
6.7
27.3
29.7
36.4
10.2
26.8
32.8
30.2
7.7
21.1
45.8
25.4
10.0
21.4
35.9
32.7
8.0
81.0
6.8
4.2
9.1
53.3
9.7
27.9
5.5
63.5
10.7
20.3
4.9
62.7
11.3
21.1
8.0
61.0
9.5
21.5
33.5
36.3
27.5
2.7
21.0
27.1
32.0
19.9
18.8
46.7
28.5
6.1
18.5
47.4
28.1
6.0
30.3
38.7
28.2
2.8
19.5
41.8
29.2
9.6
22.5
47.3
30.2
—
40.1
41.9
18.0
—
17.0
47.9
9.1
26.1
13.3
43.8
13.5
29.4
14.1
42.3
22.5
21.1
21.6
40.8
12.9
24.7
Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996
ARTICLES 185
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The smoking habits of the study population are shown in
Table 3. The gender differences in the smoking habits of our
study population were consistent with the hypothesis of a
greater susceptibility to lung cancer by females. In general,
females with lung cancer had less exposure to cigarette smoke
than males with lung cancer. For example, women among both
case and control subjects, particularly those aged 55 years or
older, were more likely to have never smoked than men. Among
case subjects, the highest proportion of those who reported
themselves to be never-smokers (compared with ever-smokers)
was in women with adenocarcinoma and with age 55 years or
older (19% in women versus 10% in men), while those with
small-cell/oat cell carcinoma had the lowest frequency of neversmokers in both sexes (0% in males versus 2% in females). In
addition, among both case and control subjects, fewer women
than men reported inhaling deeply or inhaling at all, smoking
more than 75% of each cigarette, and smoking within 15
minutes of awakening; moreover, compared with men, nearly
twice as many women than men started smoking past the age of
20. Finally, both the mean tar yield per cigarette and the mean
number of cigarettes smoked per day were higher for men than
for women regardless of their case-control status.
Table 3. Smoking habits of study population
Females
Males
Adenocarcinoma
(n = 418), %
Small-cell/
oat cell
carcinoma
(n=182), %
0.9
2.9
9.7
10.0
Inhalation
Never
Slightly
Moderately
Deeply
4.2
7.0
47.1
41.9
Proportion of cigarette
smoked
All
Less than half
Small-cell/
oat cell
carcinoma
(n=!42), %
Controls
(n= 1122),%
Squamous/
epidermoid
carcinoma
(n= 165),%
Adenocarcinoma
(n = 384), %
0.0
0.0
45.9
55.3
5.4
8.3
8.5
19.0
0.0
3.0
61.4
75.4
1.9
5.1
56.2
37.1
3.9
4.5
56.7
35.3
8.2
14.5
48.8
28.5
8.6
6.5
53.9
30.9
5.0
10.4
54.9
29.7
6.5
15.9
39.8
34.8
12.8
15.8
52.7
18.5
33.6
26.7
29.2
31.1
38.5
23.5
25.9
30.3
29.3
25.3
31.3
30.0
31.4
30.0
29.6
36.9
First cigarette after
awakening
<15 min
>15 min
62.1
37.9
53.5
46.5
56.7
43.3
42.8
57.2
62.1
37.9
52.8
47.2
57.7
42.3
34.9
65.1
Age started smoking
<!7y
18-20 y
>21 y
67.6
21.0
11.4
64.1
23.5
12.4
59.3
29.4
11.3
56.6
26.1
17.2
47.1
32.0
20.9
46.0
34.7
19.3
49.6
27.3
23.0
33.1
34.2
32.7
Tar yield per cigarette
Mean
Standard deviation
14.7
4.8
14.6
5.0
14.6
5.8
14.3
5.0
14.1
4.4
13.7
4.9
13.4
5.5
13.2
4.9
Cigarettes smoked
per day
Mean
Standard deviation
30.7
11.8
30.0
12.7
30.0
11.0
25.3
11.2
26.2
11.0
24.2
9.8
26.4
10.0
19.2
9.7
Squamous/
epidermoid
carcinoma
(n = 397), %
% who never smoked
Age <55 y
Age >55 y
Controls
(n = 948), %
Females
Males
No. of
cases
No. of
controls
Odds
ratiot
95%
confidence
interval
Female odds ratio/
male odds ratio
—
15.4-71.0
17.3-78.3
25.4-116.2
38.3-173.2
1.9-2.3
12
45
53
30
20
673
146
81
30
10
1.0
24.5
38.5
56.2
129.3
3.2
—
12.0-49.7
19.5-76.0
26.2-120.5
47.3-353.2
2.7-3.8
1.5*
1.0
6.5
24.1
48.9
82.1
2.6
—.
2.7-15.4
11.0-52.4
22.9-100.7
39.5-170.9
2.3-2.9
12
13
43
1.0
11.9
26.4
48.8
95.2
3.0
—
4.9-28.8
13.1-53.4
24.9-95.8
43.4-209.0
2.6-3.5
1.2
1.0
14.1
16.0
38.9
66.8
2.1
—
7.6-26.4
9.5-27.0
23.1-65.3
36.8-121.3
1.9-2.3
12
11
52
75
15
1.0
9.3
33.0
74.9
85.3
2.9
—
3.9-22.1
16.3-66.6
37.0-151.5
29.5-247.1
2.5-3.3
1.4+
No. of
cases
No. of
controls
Odds
ratiot
95%
confidence
interval
Tar. kg
0
1-2
3-5
6-8
>9
Dose—response
8
72
85
85
124
476
141
140
95
92
1.0
33.1
36.8
54.3
81.5
2.1
Pack-years
0
1-19
20-39
40-49
>50
Dose-response
8
16
58
114
192
Exposure measure
Most recent No. of
cigarettes smoked
per day
0
1-10
11-20
21-40
>41
Dose-response
8
31
87
169
94
476
147
139
141
138
476
235
188
174
49
58
39
673
76
105
68
25
673
69
125
68
13
*Referent group: never-smokers.
tAdjusted for age.
tSignificant at P<.05.
186
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Table 4. Odds ratios for lung cancer in current smokers versus never-smokers: squamous/epidermoid carcinoma*
males and females, respectively), produced slightly lower ORs
than those obtained for adenocarcinoma alone. Nevertheless,
despite the higher nonsmoking rates for female case subjects,
the gender difference remained statistically significant for all
three exposure measures; dose-response ORs were 1.5-fold
higher for tar yield and 1.3-fold higher for both pack-years and
number of cigarettes smoked per day in women than in men.
Alternatively, we recomputed the ORs listed in Tables 4 and
5 by substituting light smokers for never-smokers as the referent
category to reduce the effect of potential differences in base-line
exposure to lung carcinogens between males and females. Although the resultant RR estimates computed at individual exposure levels were considerably lower than before, the values of
the dose-response ORs and the magnitude of the male-female
differences in ORs remained unchanged. Nonetheless, these differences were no longer statistically significant, which is not
surprising in light of the reduction in statistical power that
resulted from the exclusion of never-smokers from this analysis.
Effect of Body Weight on ORs for Lung Cancer
As shown in Fig. 2, adjustment for body weight (reported as
of 5 years before diagnosis of the current disease) had virtually
no effect on either the magnitude or the male-female differences in the ORs for any of the major histologic types of lung cancer examined. Subsequent adjustments for height and body mass
index caused similarly minor changes in the ORs at individual
levels of exposure, while all dose—response ORs remained unchanged by any of these adjustments.
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moid type, at individual levels of exposure and also for the
dose-response (OR = 1.8-2.0 for men and 2.5-2.9 for women)
(Table 5). The dose-response OR for women was significantly
higher (1.3-fold to 1.6-fold) than for men by all three exposure
measures. As with squamous/epidermoid carcinoma, the gender
difference in the dose-response OR for adenocarcinoma was
greatest when estimated over cumulative exposure to tar.
Similarly, all three dose-response ORs for small-cell/oat cell
carcinoma were significantly higher (1.5-fold to 1.7-fold) for
women than for men (4.0 for women versus 2.3 for men for tar
yield, 3.7 for women versus 2.5 for men for pack-years, and 3.2
for women versus 2.1 for men for number of cigarettes smoked
per day). As before, the gender difference in OR was most
prominent when estimated over cumulative exposure to tar.
When the category squamous/epidermoid carcinoma was
combined with the categories of small-cell/oat cell carcinoma
and large-cell carcinoma (Kreyberg I), the gender differences
were greater than those for squamous/epidermoid carcinoma
alone, and the dose-response ORs were significantly higher for
females by all three exposure measures: 1.7-fold higher for tar
yield and 1.4-fold higher for both pack-years and number of
cigarettes smoked per day (Fig. 1). This is likely to be due to the
larger sample sizes and narrower CIs, in addition to the higher
ORs of small-cell/oat cell and large-cell carcinomas.
The combination of the category bronchiolar and alveolar cell
carcinomas with that of adenocarcinoma (Kreyberg II), due to
the higher percentage of never-smokers among case subjects
with bronchiolar and alveolar cell carcinomas than among those
with adenocarcinoma (7% versus 6% and 24% versus 11% for
Table 5. Odds ratios for lung cancer in current smokers versus never-smokers: adenocarcinoma*
Males
Females
No. of
cases
No. of
controls
Odds
ratiot
95%
confidence
interval
Tar, kg
0
1-2
3-5
6-8
>9
Dose-response
38
85
80
93
99
476
141
140
95
92
1.0
7.1
6.8
12.4
14.7
1.8
Pack-years
0
1-19
20-39
40-49
>50
Dose-response
38
29
71
127
145
Exposure measure
Most recent No. of
cigarettes smoked
per day
0
1-10
11-20
21-40
>41
Dose-response
38
25
105
166
76
476
147
139
141
138
476
235
188
174
49
No. of
cases
No. of
controls
Odds
ratiot
95%
confidence
interval
Female odds ratio/
male odds ratio
—
4.6-11.0
4.4-10.5
8.0-19.2
9.4-23.1
1.7-2.0
58
122
101
66
26
673
146
81
30
10
1.0
11.6
13.9
25.4
33.2
2.9
—
7.8-17.1
9.3-20.9
15.2-42.2
15.0-73.3
2.5-3.3
1.6*
1.0
2.4
5.6
11.6
13.8
2.0
—
1.4-4.1
3.6-8.7
7.7-17.6
9.2-20.9
1.8-2.2
58
37
99
122
66
1.0
6.8
11.2
21.4
32.7
2.5
—
4.1-11.4
7.5-16.8
14.3-32.2
19.0-56.2
2.3-2.8
1.3$
1.0
4.4
7.2
12.1
19.3
1.8
—
2.5-7.6
4.9-10.4
8.4-17.4
12.0-30.3
1.7-1.9
58
26
127
142
31
1.0
4.5
14.2
27.2
34.3
2.5
—
2.7-7.7
9.6-20.9
17.8-41.6
16.2-72.5
2.2-2.8
1.4*
673
76
105
68
25
673
69
125
68
13
*Referent group: never-smokers.
tAdjusted for age.
tSignificant al P<05.
Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996
ARTICLES
187
A
B
<Ddds ratios
Odds ratios
150
150
Females^
/
100
Kreyberg I
Jr
P<.05
/
100
50
<£>
Females
Sr
/ ^
Kreyberg II^ ~"
P<05
Males
3-5
6-8
-"
/ ^
9+
3-5
1-2
Fig. 1. Sex-specific odds ratios
for Kreyberg I-type (690 male
and 397 female case subjects)
versus Kreyberg Il-type (435
male and 414 female case subjects) lung cancer, adjusted for
age only (A) or adjusted for age
plus prediagnostic body weight
(B). P values are based on overall gender differences in odds
ratios.
Females
Kreybergll
&^
B-"^^
1-2
P<.05
Kreyberg I
/Males
-y
50
Females/
Males
6-8
9+
Total tar (kg)
Total tar (kg)
The results of the present study essentially confirm our initial
finding that, given the same level of lifelong exposure to
The aim of this more detailed re-evaluation of our data was to cigarette smoke, women had an approximately 1.5-fold higher
further explore the feasibility of the hypothesis of a gender dif- estimated RR of developing lung cancer than men (8). Furtherference in the RR for lung cancer, as our earlier results (8) sug- more, the gender difference in estimated RR (a) was statistically
gested. The current study included 616 additional case subjects significant for all three major histologic types of lung cancer, aland an equivalent number of control subjects accrued since though slightly greater for adenocarcinoma and small-cell/oat
1988, and the histologic classifications were no longer limited to cell carcinoma than for squamous/epidermoid cancer; (b) inKreyberg I and II. Finally, to avoid biasing the RR estimates creased with increasing levels of lifelong exposure to cigarette
(15,16), we decided to exclude the small number of non- smoke; (c) was most pronounced when differences in Federal
Caucasians from our data.
B
A
Odds ratios
Odds ratios
150
150
•
Females /
100
Females/
100
/
-
/
/P<.05
Squamous/
epidermoid
/
/
Squamous/
epidermoid
50
' Ai^-*—
ARTICLES
Females^
P<.05
A/
Males
3-5
6-8
Total tar (kg)
188
yf
jn
^ - - - ^
Ade no ca re inoiga—
1-2
si-
/ / Males
Females
.—
<1
•
Wales
J/
50
/P<.O5
Fig. 2. Sex-specific odds ratios
for squamous/epidermoid carcinoma of the lung (397 male
and 165 female case subjects)
versus adenocarcinoma of the
lung (418 male and 384 female
case subjects), adjusted for age
only (A) or adjusted for age
plus prediagnostic body weight
(B). P values are based on overall gender differences in odds
ratios.
9+
<1
^ ^
Adenocarcjuorfi
_,
1-2
Qi
3-5
P<.05
Males
6-8
9*
Total tar (kg)
Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996
Downloaded from jnci.oxfordjournals.org at Maine Department of Public Health on June 14, 2011
Discussion
Trade Commission-reported tar yield, combined with duration
of smoking and number of cigarettes smoked per day, were included in the comparison; and (d) was unrelated to differences
in body weight and height.
Our results further suggest that the apparent higher RR for
lung cancer in women may apply to nonsmokers as well, since
the proportion of never-smoking lung cancer patients was more
than twice as high in women than in men—surpassing the
gender difference in smoking prevalence during the past several
decades. All of these findings suggest that women may have a
greater susceptibility to the effects of lung carcinogens than
men.
Potential Confounders and Biases
Downloaded from jnci.oxfordjournals.org at Maine Department of Public Health on June 14, 2011
We considered the possibility that the observed gender differences may be due to unequal base-line exposures, differences
in body size, or incorrect estimates of exposure to tobacco
smoke.
(a) Differences in base-line exposure. It has been suggested
that the lower ORs due to smoking in males may actually be the
result of men's higher base-line risk caused by occupational exposures to lung carcinogens (22,23). On the contrary, both our
current and previous (8) results, as well as results obtained by
McDuffie et al. (7), showed that women with lung cancer were
two to three times more likely to have never smoked than men.
This finding suggests that women, not men, may have a higher
base-line risk. Because of the higher smoking rates of men, nonsmoking married women are more likely to have been exposed
to passive smoke than their male counterparts. In fact, in our
data, the highest frequency of lung cancer cases occurred among
widows, regardless of their smoking status; this finding raises
the possibility of smoking-related deaths among their heavily
smoking former spouses and consequent passive smoking by the
widows themselves. Thus, given a greater base-line exposure,
the dose-response ORs over active smoking should be lower,
rather than higher, in women. In fact, we found women to have
a higher estimated RR due to smoking, regardless of whether
light smokers or never-smokers were used as the reference
category.
(b) Male-female differences in body size. It is recognized
that lung cancer risk and smoking are both inversely related to
obesity (24) and that women tend to be smaller than men. However, adjustments for body weight and size did not alter the differences in ORs between males and females, indicating that the
association between lung cancer and body size could not account for the observed gender differences in RR.
(c) Biased or incorrect measures of smoking exposure. We
further considered the possibility that, while women smoked
fewer cigarettes and chose cigarettes of lower tar and nicotine
yield, their exposures to tobacco carcinogens may have been underestimated as a result of smoking behavior affecting the actual
amount of tar inhaled. In fact, the lack of a negative association
between the number of cigarettes smoked per day and the
Federal Trade Commission-reported tar and nicotine yield in
both sexes failed to provide evidence of nicotine compensation
through smoking. Furthermore, in both the case subjects and the
control subjects, we found that men tended to inhale more deeply and to have started smoking at an earlier age than women.
Thus, since we did not adjust for depth of inhalation and age at
smoking onset, the RR for women, compared with that for men,
due to smoking was likely to have been underestimated by our
results.
Nevertheless, the amount of tar inhaled is also influenced by
puff frequency and puff volume (25), both of which may differ
by gender. Work is currently under way at the American Health
Foundation to determine the ratio of actual to Federal Trade
Commission-reported milligrams of tar inhaled by nicotine
yield, race, and sex. When this information becomes available,
we will include it in our index of lifelong exposure to cigarette
tar.
An additional possible source of error in our exposure estimates was recall bias, since it is impossible to obtain direct estimates of the validity of information regarding past smoking
habits. Nonetheless, based on measures of reproducibility obtained through regular monthly re-interviews conducted on random samples of 10% of the new study participants, the level of
agreement for responses related to smoking was found to be
high (correlation coefficient = .93) (26), which may be construed as an indirect indication of high validity.
The accuracy of our measure for lifelong exposure to tar is
somewhat compromised by the fact that the tar yields are currently those reported in the 1977 and 1988 Federal Trade Commission reports (18). In fact, since tar yields within specific
cigarette brands have continually decreased during the past three
decades (27), the exposure of long-term, heavy smokers tends to
be underestimated by this measure. Nevertheless, since the
majority of long-term, heavy smokers are men, this bias is expected to diminish, rather than to inflate, women's RRs due to
smoking.
An additional limitation is that, in the past, we did not have
the lung cancer histologies verified by an independent review
panel; instead, we simply recorded the individual pathologists'
classifications in our data. However, the likelihood of bias is
reduced by the fact that the frequencies of the various histologies for both sexes are consistent with those published by
the Surveillance, Epidemiology, and End Results (SEER) Program1 during the same period (28).
Relevant Findings by Other Investigators
During the past decade, several studies (5-13) have found a
greater susceptibility to lung carcinogens by women smokers.
Notably, a study by Risch et al. (10) reported male and female
risk ratios that were remarkably consistent with our earlier (8)
and current results. In fact, a gender difference in estimated RR
was observed for all major histologic types by most investigators (5,8,10), with the exception of Osann et al. (//), who
found this difference only for small-cell carcinoma. Furthermore, in agreement with our RR estimates obtained over various
levels of current number of cigarettes smoked per day, higher
RRs for women were observed even without adjustment for tar
yield (5-13) and duration of exposure (8,9). Thus, since men are
more likely to be long-term, heavy smokers than women, this
implies that some of these studies may have underestimated the
actual gender difference in RR estimates.
Begg et al. (12) provided a broader indication of a femalemale difference in susceptibility to tobacco carcinogens. Their
Journal of the National Cancer Institute, Vol. 88, No. 3/4, February 21, 1996
ARTICLES
189
Potential Biological Explanations
The biological plausibility of a higher susceptibility to tobacco carcinogens in women is supported by several laboratory investigations. These investigations are related to nicotine
metabolism, cytochrome P-450 enzymes, and hormonal factors.
(a) Gender differences in nicotine metabolism. Clinical
studies (33,34) have indicated that the total plasma clearance of
nicotine, normalized for body weight, is lower in women than in
men. Furthermore, Hecht and Hoffmann (35) showed that
nicotine can be a precursor for tobacco-specific carcinogens.
Clinical observations of a lower nicotine metabolism by women
are supported by several studies on rats (36-38) and by one
study on stumptailed macaques (39). However, there is at least
one study (40), conducted on a group of smokers in the U.K.,
that found no gender difference in nicotine exposure.
(b) Male-female variations in cytochrome P-450 enzymes.
Recent evidence shows that cytochromes P-450 1A1, 1A2, 2E1,
2A6, and perhaps other cytochrome P-450 enzymes in human
liver are involved in the bioactivation of genotoxic components
in cigarette smoke condensate, including polycyclic aromatic
hydrocarbons, certain nitrosamines, and aromatic amines (41).
Thus, one factor modulating the development of carcinogenesis
is believed to be interindividual differences in the activity of
these enzymes (41). In fact, as early as 1974, Kato (42) suggested that " . . . the sex difference in the oxidation of drugs by
liver microsomes is due mainly to the higher binding capacity
of cytochrome P-450 of male rats." In an even earlier study
published in 1967, Schenkman et al. (43) noted that " . . . microsomes isolated from the livers of male rats had twice the
magnitude of substrate (hexobarbital and aminopyrine) binding than did microsomes isolated from the livers of female
rats." Consequently, differences in the activity of these enzymes
190
ARTICLES
could also influence the lung cancer susceptibility in men and
women.
In more recent years, evidence has been accumulating that
cytochrome P-450 in liver microsomes plays a central role as a
drug-metabolizing enzyme and that there are sex-dependent differences in the properties of this enzyme (44). For example, in
comparing cytochrome P-450 isozyme-selective bioactivation of
1,1-dichloroethylene in the lungs of female and male mice, Lee
and Forkert (45) found that CYP2E1-dependent p-nitrophenol
hydroxylation was significantly higher in microsomes from
females than from males, suggesting that females may be at
slightly greater risk for 1,1-dichloroethylene-induced pneumotoxicity. Other investigators observed that lung microsomes
from male rats had increased activity of P4502C11 (46); that 1benzylimidazole produced a statistically significant increase in
P-450 2B1/2 in male rats, but not in female rats (47); that the
levels of cytochrome P-450 enzymes differ in the hair follicles
of men and women (48); and that castration of male rats
markedly reduced microsomal sulfamethazine hydroxylation
rates, suggesting that the male-specific P-4502C11 enzyme
plays an important role in the hydroxylation of sulfamethazine
(49).
In addition, Ryberg et al. (50) found that the DNA adduct
levels were higher in female than in male lung cancer
patients after adjustment was made for smoking dose and that
" . . . patients with high adduct levels generally had shorter duration of smoking and/or lower smoking dose before the clinical
onset of the disease." This observation suggests that women are
exposed to higher levels of nicotine than men and thus may have
a greater RR for tobacco-induced lung cancer.
(c) Effect of hormones on tumor development. Support for
the hypothesis that endogenous and exogenous hormones play
an important role in carcinogenesis comes from both
epidemiologic observations and basic research findings. In a
large-scale epidemiologic cohort study, Adami et al. (57)
reported a slightly, although not significantly, elevated RR (RR
= 1.3; 95% CI = 0.9-1.7) for lung cancer in women who
received estrogen replacement therapy, but no allowance was
made for histologic type or smoking. Gao et al. (52) reported
short menstrual cycles to be associated with lung cancer risk in
Chinese women, although our data do not confirm this. Using
data from the American Health Foundation's long-standing
case-control study on smoking and lung cancer (also used in the
present study), Taioli and Wynder (53) found both an elevated
risk due to hormone replacement (OR = 1.7; 95% CI = 1.0-2.5)
and a statistically significant synergy between the effects of
smoking and estrogen replacement therapy with regard to
adenocarcinoma of the lung. We plan to further investigate this
association as our data on estrogen replacement therapy continue to accumulate with respect to estrogen exposure. Finally,
in our current results, women 55 years old or older with lung
cancer, particularly with adenocarcinoma, were nearly twice as
likely to be never-smokers than younger women with lung cancer, while no comparable age-related difference in smoking was
found either among male lung cancer case subjects or among
female control subjects (Table 3).
That sex hormones affect cytochrome P-450 was already suggested in 1974 by Kato (42), who stated: "The content of
Journal of the National Cancer Institute, Vol. 8&, No. 3/4, February 21,1996
Downloaded from jnci.oxfordjournals.org at Maine Department of Public Health on June 14, 2011
results suggested that women may have higher RRs for developing second primaries of most smoking-related cancers, including
those of the esophagus, urinary bladder, and kidney, in addition
to lung.
On the other hand, some studies either found a lower RR in
women compared with men (29) or did not observe a gender difference in RR for lung cancer at all (30,31). These include three
major cohort studies: the American Cancer Society's Second
Cancer Prevention Study (29), the British Physicians Study
(30,31), and an ongoing study conducted by the U.S. National
Cancer Institute (32). The first of these studies (29) found higher
ORs for male current smokers and ex-smokers than for female
current smokers and ex-smokers, while the other two studies
(30,31) found no difference in RR between the sexes. However,
because men have traditionally smoked more than women, a
higher susceptibility for females could well have been
camouflaged by their lower exposures. In fact, none of these
studies adjusted for duration of smoking or tar yield in their RR
estimates. In addition, the RRs for men are likely to have been
inflated by a lower proportion of never-smokers among male
lung cancer case subjects. Nevertheless, if women are, in fact,
more susceptible to lung cancer than men, this should become
increasingly evident as gender differences in smoking exposure
continue to diminish.
B
Smoking prevalence, %
Lung cancer incidence
60
Fig. 3. A) Current cigarette
smoking prevalence in U.S.
males and females 18 years old
or older. Source: Centers for
Disease Control and Prevention, National Center for Health
Statistics; data from the National Health Interview Survey
(/). B) Surveillance, Epidemiology, and End Results Program incidence rates for
invasive lung and bronchus
cancers for all U.S. males and
females (2). Rates are per
100 000 and are age adjusted to
the 1970 U.S. standard population.
MALES
90
Males
40
60
20
30
_!
1965
1974
1983
1991
1973
Years
)chrome P-450 in microsomes is increased 20-30% by
rogen," and ".. . castration of male rats decreases both the
iation of some drugs and the binding capacity of cytochrome
50 for these compounds." In addition, various hormones
e been shown to be involved in the induction and developlt of lung tumors. For example, repeated injections of
fied growth hormone into female rats induced lymphosarlas of the lung, and injections of estradiol into guinea pigs
iced lung adenomas, while concomitant administration of
xycorticosterone, cortisone, progesterone, and testosterone
rented estrogen-induced lung tumorigenesis in guinea pigs
i. Thus, estrogen-induced lung tumors in female guinea pigs
hormone responsive; consequently, the levels of sex hories and their influence on the metabolism of tobacco carigens are likely to affect the susceptibility to lung cancer in
es and females.
I summary, our present results agree with the hypothesis
, dose for dose, females are more susceptible to the effects of
icco carcinogens than males. Furthermore, this difference
; not appear to be the result of external factors, such as ocitional exposure or smoking behavior, and it does not seem
e related to body size or lung size. A more plausible exation may be variations in physiologic mechanisms, such as
;rences in metabolic activation and detoxification of lung
inogens. In view of the continued high smoking prevalence
growing incidence of lung cancer among women (Fig. 3),
pounded by accumulating evidence of their increased susibility to tobacco carcinogens, effective programs for smokprevention and cessation must have a high priority on our
ida for women's health issues.
erences
Healthy People 2000 Review. Washington (DC): US Department of Health
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Notes
Editor's note: SEER is a set of geographically defined, population-based
central tumor registries in the United States, operated by local nonprofit organizations under contract to the National Cancer Institute (NCI). Each registry
annually submits its cases to the NCI on a computer tape. These computer tapes
are then edited by the NCI and made available for analysis.
Supported by Public Health Service grant CA32617 from the National Cancer
Institute, National Institutes of Health, Department of Health and Human Services.
We thank Drs. S. S. Hecht and D. Hoffmann from the American Health Foundation and Dr. C. B. Begg from the Memorial Sloan-Kettering Cancer Center for
reviewing this manuscript and for providing valuable comments and suggestions
that have been incorporated in the final version.
Manuscript received May 24, 1995; revised September 20, 1995; accepted October 26, 1995.
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